Risperidone or Paliperidone Implant Formulation

ABSTRACT

The present invention is directed to an injectable intramuscular depot composition suitable for forming an in situ solid implant in a body, comprising a drug which is risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination, a biocompatible copolymer based on lactic and glycolic acid having a monomer ratio of lactic to glycolic acid of about 50:50 and a DMSO solvent, wherein the composition releases the drug with an immediate onset of action and continuously for at least 4 weeks and wherein the composition has a pharmacokinetic profile in vivo that makes it suitable to be administered each 4 weeks or even longer periods.

CROSS-REFERENCE TO EARLIER FILED APPLICATIONS

The present application is a continuation-in-part of and claims thebenefit of PCT/EP2013/061320, filed May 31, 2011, which claims thebenefit of EP 12170362.3 filed May 31, 2012, and the present applicationis also a continuation-in-part of and claims the benefit of U.S. Ser.No. 13/690,647 filed Nov. 30, 2012, which claims the benefit ofPCT/EP2011/059000, filed May 31, 2011, which claims the benefit of EP10382154.2 filed May 31, 2010, and the present application also acontinuation-in-part of and claims the benefit of U.S. Ser. No.13/690,707, filed Nov. 30, 2012, which claims the benefit ofPCT/EP2011/059001, filed May 31, 2011, which claims the benefit of EP10382153.4 filed May 31, 2010, the entire disclosures of which arehereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to extended release pharmaceuticalcompositions for intramuscular injection comprising the drugrisperidone, its pharmaceutically acceptable salts and/or itsmetabolites like as paliperidone, wherein the composition releases thedrug with an immediate onset of action and continuously for at least 4weeks, and wherein the composition has a pharmacokinetic profile in vivothat makes it suitable to be administered each 4 weeks or even longerperiods. Specifically, the present invention is related to compositionsfor injectable in-situ forming biodegradable implants comprisingrisperidone and/or paliperidone.

BACKGROUND OF THE INVENTION

Risperidone and paliperidone are atypical antipsychotic drugs withbenzisoxazole and piperidine functional groups, which act as strongdopaminergic antagonist and selective serotonin receptor antagonist.Risperidone is FDA approved for the treatment of schizophrenia since1993. It is the only drug presently approved for the treatment ofschizophrenia in young people under 18 years, and together with lithium,for the treatment of bipolar disorders in children/youth ages between10-18 years old. Conventional risperidone therapy of schizophreniainvolves daily oral tablets, although it is also available as a solutionand orally disintegrating tablets.

In fact, one of the intrinsic problems that risperidone orpaliperidone-targeted patients usually face is the dissociation of someschizophrenic patients from the treatment, moreover when it consists ofa daily medication, leading to irregular or inconstant treatments andfavoring the appearance of psychotic crisis. Moreover, this kind oftherapy gives rise to high differences in the plasma levels (measured asthe difference between Cmax and Cmin) in patients, therefore usuallyaffecting the patient's mood.

Risperidone and paliperidone are therefore good drug candidates forincorporation into sustained delivery devices, where the patients wouldbe covered or treated for long time periods with just one dose andwithout the need of caregivers to pay attention to a daily medication,and where more homogeneous plasma levels in the patient are desirable.Other indications may involve bipolar mania and schizoaffectivedisorder, and its possible use in autism and Asperger's syndrome andTourette's disorder may be of benefit to the patients.

Risperidone was initially marketed as Risperdal® and recently becamegeneric. Currently, the long-acting injectable risperidone formulation,Risperdal Consta®, is the first depot atypical antipsychotic drug in themarket. It is an intramuscular risperidone-containing PLGAmicroparticles formulation and is intended to deliver therapeutic levelsof risperidone by bi-weekly administrations. However, due to theinherent lag phase of most microparticle based products, the patient isrequired to supplement the first weeks with daily doses of oralrisperidone after first administration. Approximately three weeks aftera single intramuscular injection of Risperdal Consta® and concurrentdaily doses of oral risperidone, the microspheres release sufficientrisperidone in the systemic circulation that the patient can discontinuesupplementation with daily doses of the oral therapy. However, thisperiod of oral supplementation could be a risk factor of non-compliance.Also, the presence on the body of two doses at the same time could be apotential risk of adverse events, such as irregular formulationbehaviour and toxicity.

Paliperidone recently received marketing approval as the first oralatypical antipsychotic with an extended release, which is achieved by anosmotic-controlled release oral delivery system. Paliperidone ER(WO2006/17537) is marketed as Invega Sustenna® and unsaturatedderivatives thereof are described in WO2008/128436. Other extendedrelease oral dosage forms for paliperidone are under development. Duethe presence of a secondary hydroxyl group, paliperidone may be providedas a prodrug. WO2009/15828 details acid-labile low molecular weightprodrugs of paliperidone intended to undergo hydrolysis in the stomach.

Therefore, in view of the state of the art, it is of interest to developvery long-acting, injectable depots of risperidone and/or paliperidone.There is great need to improve the compliance factor particularly in thetreatment of schizophrenia. The development of once-weekly or evenlonger acting injectable depot formulations of those drugs will mark asignificant step forward to ensure continuous and steady supply of theeffective medication. In U.S. Pat. No. 5,965,168 application isdescribed compounds of formula I which are formulated in sustainedrelease microparticles. Risperidone is mentioned as the preferredcompound and risperidone is used as basis for all experiments therein.FIG. 5 therein shows the plasma concentration time curves for the activemoiety (sum of risperidone and paliperidone) after intramuscularinjection of risperidone depot.

WO2008/153611 describes sustained release formulations of risperidoneand metabolites. Here, risperidone is mixed with a soluble thermoplasticpolymer, forming an encapsulating residue upon injection from whichrisperidone is slowly released. EP2234617 reveals ester-linked prodrugsof paliperidone. The substance paliperidone palmitate is approved as aonce-monthly atypical antipsychotic intramuscular injection for treatingschizophrenia and preventing recurrence of its symptoms. Paliperidonepalmitate is formulated in a submicrocrystalline form. Paliperidonepalmitate due to its dissolution rate-limited absorption exhibitsflip-flop kinetics, where the apparent half-life is controlled by theabsorption rate constant. Additionally the volume of injected drugproduct also impacts the apparent rate constant. It was also discoveredthat deltoid injections result in a faster rise in initial plasmaconcentration, facilitating a rapid attainment of potential therapeuticconcentrations. Consequently, to facilitate patients' attaining a rapidtherapeutic concentration of paliperidone it is preferred to provide theinitial loading dose of paliperidone palmitate in the deltoids. Theloading dose should be from about 100 mg-eq. to about 150 mg-eq. ofpaliperidone provided in the form of paliperidone palmitate. After thefirst or more preferably after the second loading dose injectionpatients will be approaching a steady state concentration ofpaliperidone in their plasma and may be injected in either the deltoidor the gluteal muscle thereafter. However, it is preferred that thepatients receive further injections in the gluteal muscle. US2009/163519outlines corresponding dosing regimen for long-acting injectablepaliperidone esters of the palmitate type.

Other antipsychotic depot medications are also characterized by the needfor concomitant oral medication or booster injections in order to obtaindesired plasma levels of the active drug. For example, Risperdal Consta®requires oral antipsychotic treatment during the initiation phase.

Other depot formulation is described by the international applicationWO2011/42453. This specification describes a pharmaceutical compositionfor subcutaneous injection comprising a paliperidone compound. Inparticular the composition refers to a composition in which paliperidoneis linked by an ester bondage to a hydrogel. The formulation releasespaliperidone by ester bondage cleavage and claims to release thepaliperidone with an immediate onset of action and for an extendedrelease time. Moreover, this specification relates to a pharmaceuticalcomposition for subcutaneous injection comprising a paliperidonecompound in a certain concentration.

Finally, another antipsychotic injectable depot composition is describedin the international application number WO2011/151355. This applicationis directed to a composition that can be used to deliver anantipsychotic drug such as risperidone as an injectable in-situ formingbiodegradable implant for extended release providing therapeutic plasmalevels from the first day. The composition is in the form of drugsuspension on a biodegradable and biocompatible copolymer or copolymerssolution using water miscible solvents that is administered in liquidform. Once the composition contacts the body fluids, the polymer matrixhardens retaining the drug, forming a solid or semisolid implant thatreleases the drug in a continuous manner.

SUMMARY OF THE INVENTION

Therefore, the compositions already described in the state of the art donot meet the existing needs in risperidone and or paliperidonecompositions, kits and treatments for psychiatric disorders, and therestill exists a need of compositions and devices to allow a controlled,constant release of the drug during prolonged periods of time during atleast 4 weeks without a concomitant treatment or initial doses ofrisperidone and/or paliperidone.

Aspects of the invention provide an injectable depot composition, a kitfor use in preparing the composition, a method of administering thecomposition, a method of preparing the composition, and a method oftreating a disease or disorder with the composition. The method ofadministering can be used as a method of treating. The disease ordisorder is therapeutically responsive to risperidone and/orpaliperidone.

The invention provides an injectable intramuscular depot compositionsuitable for forming an in situ solid implant in a body, the compositioncomprising a drug which is risperidone and/or paliperidone, or itspharmaceutically acceptable derivatives and/or salts in any combinationthereof, a biocompatible copolymer based on lactic and glycolic acidhaving a monomer ratio of lactic to glycolic acid in the range of 45:55to 55:45, 48:52 to 52:48 or about 50:50, i.e. 50:50±10%, and DMSO,wherein the composition releases the drug with an immediate (or rapid)onset of action and continuously for at least 4 weeks and wherein thecomposition has a pharmacokinetic profile in vivo with substantially noor with minimal burst release of the drug characterised in that thebiocompatible copolymer has a molecular weight between 30 and 46 andpreferably between 30 and 36 kDa and has an inherent viscosity in therange of 0.26-0.31 and preferably between 0.26-0.29 dl/g±10%.

The invention provides a pharmaceutical kit suitable for in situformation of a biodegradable non-particulate solid implant in a subjectin need thereof. In some embodiments, the kit comprises: a firstcontainer comprising drug, and/or a metabolite and/or a prodrug thereof;a second container comprising a biocompatible PLGA copolymer having aninherent viscosity in the range of about 0.26-0.31 dl/g or about0.26-0.29 dl/g; and a third container comprising DMSO. By mixing thecontents of the third container with the contents of the secondcontainer, a polymeric solution is formed, which solution is then mixedwith the contents of the first container to form the injectablecomposition as described herein. In some embodiments, the copolymer anddrug (and/or a metabolite and/or a prodrug thereof) are included in afirst container, and DMSO is included in a second container. In someembodiments, the containers are syringes and the mixing of theircontents may be performed by direct or indirect connection followed bymoving the plungers of the syringes forwards and backwards. Embodimentsof the invention include those wherein: a) drug and/or copolymer ispresent in solid form in a container prior to mixing with the solvent;or b) drug and/or copolymer is present in particulate form or as alyophilisate in a container prior to mixing with the solvent (DMSO).

The invention includes a method of administering the injectablecomposition, comprising: a) administering an amount of sustained releaseinjectable depot composition comprising a dose of drug, metaboliteand/or derivative thereof; and b) after about 4 weeks, about 5 weeks, orabout 6 weeks, from the prior dose, administering an amount of sustainedrelease injectable depot composition comprising a dose of drug,metabolite and/or prodrug thereof. The invention comprises embodimentswherein step b) is repeated one or more times.

The invention also includes a method of treating a disease or disorderthat is therapeutically responsive to risperidone and/or paliperidoneand/or a prodrug thereof, the method comprising: a) administering to asubject in need thereof an amount of sustained release injectable depotcomposition comprising a dose of drug, metabolite and/or derivativethereof; and b) after about 4 weeks, about 5 weeks, or about 6 weeks,from the prior dose, administering to the subject an amount of sustainedrelease injectable depot composition comprising a dose of drug,metabolite and/or prodrug thereof. The invention comprises embodimentswherein step b) is repeated one or more times.

The period of time from one dose administration to another is a dosingperiod. A treatment period comprises plural dosing periods.

The invention includes all combinations of aspects, embodiments andsub-embodiments disclosed herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1.—Active moiety levels profile in dog after the administration ofthe risperidone formulation described in example 1 to Beagle dogs (n=3).Dose is 2.5 mg/kg. Results are expressed as ng/ml plasma values ofactive moiety versus time. The table describes Area Under the Curve(AUC) of active moiety plasma levels versus time. AUC all as well as AUCvs three different time frames are included. Units are expressed inh*ng/ml.

FIG. 2.—Active moiety levels profile in dog after the administration ofthe risperidone formulation described in example 2 to two cohorts ofBeagle dogs (each cohort n=6). Doses were 2.5 and 5 mg/kg. Results areexpressed as ng/ml plasma values of active moiety versus time. The tabledescribes Area Under the Curve (AUC) of active moiety plasma levelsversus time. AUC all as well as AUC vs three different time frames areincluded. Units are expressed in h*ng/ml.

FIG. 3.—Active moiety levels profile in dog after the administration ofthe risperidone formulation described in example 3 to Beagle dogs (n=3).Dose is 2.5 mg/kg. Results are expressed as ng/ml plasma values ofactive moiety versus time. The table describes Area Under the Curve(AUC) of active moiety plasma levels versus time. AUC all as well as AUCvs three different time frames are included. Units are expressed inh*ng/ml.

FIG. 4.—Active moiety levels profile in rabbit after the administrationof the risperidone formulation described in example 4 to White NewZealand rabbits (n=3). Dose is 5 mg/kg. Results are expressed as ng/mlplasma values of active moiety versus time. The table describes AreaUnder the Curve (AUC) of active moiety plasma levels versus time. AUCall as well as AUC vs three different time frames are included. Unitsare expressed in h*ng/ml.

FIG. 5.—Active moiety levels profile in dog after the administration ofthe risperidone formulation described in example 5 to Beagle dogs (n=3).Dose is 2.5 mg/kg. Results are expressed as ng/ml plasma values ofactive moiety versus time. The table describes Area Under the Curve(AUC) of active moiety plasma levels versus time. AUC all as well as AUCvs three different time frames are included. Units are expressed inh*ng/ml.

FIG. 6.—Active moiety levels profile in dog after the administration ofthe risperidone formulation described in example 6 to Beagle dogs (n=3).Dose is 2.0 mg/kg. Results are expressed as ng/ml plasma values ofactive moiety versus time. The table describes Area Under the Curve(AUC) of active moiety plasma levels versus time. AUC all as well as AUCvs three different time frames are included. Units are expressed inh*ng/ml.

FIG. 7.—Active moiety levels profile in dog after the administration ofthe risperidone formulation described in example 7 to Beagle dogs (n=3).Dose is 2.0 mg/kg. Results are expressed as ng/ml plasma values ofactive moiety versus time. The table describes Area Under the Curve(AUC) of active moiety plasma levels versus time. AUC all as well as AUCvs three different time frames are included. Units are expressed inh*ng/ml.

FIG. 8.—Paliperidone levels profile in dog after the administration ofthe paliperidone formulation described in example 8 to Beagle dogs(n=3). Dose is 1.5 mg/kg. Results are expressed as ng/ml plasma valuesof paliperidone versus time. The table describes Area Under the Curve(AUC) of paliperidone plasma levels versus time. AUC all as well as AUCvs three different time frames are included. Units are expressed inh*ng/ml.

FIG. 9.—Drawing of a kit suitable for the preparation of risperidone andpaliperidone compositions comprising two male syringes linked by aconnector. Polymer+risperidone are contained in one syringe and DMSOfilled in the second syringe

FIG. 10.—Drawing of a kit suitable for the preparation of risperidoneand paliperidone compositions comprising a female syringe linked to amale syringe. Polymer+risperidone can be contained in one syringe andDMSO filled in the second syringe. Preferably female syringe containspolymer+risperidone as a solids and male syringe is filled with DMSO.

FIG. 11.—Loss of molecular weight percentage in the custom design. Themolecular weight of the polymer can be varied by irradiating it with acertain radiation dose. The table describes the percentage of loss ofpolymer weight versus radiation dose.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified, the term drug, metabolite and prodrugthereof are used interchangeably. In general, the term drug encompassesa metabolite and prodrug thereof.

As used herein and unless otherwise specified, the drug or activeingredient included in the injectable composition can be present in freebase, salt, amorphous, crystalline, anhydrous, hydrate, optically pure,optically enriched or racemic forms thereof. Combinations of thesevarious forms are also within the scope of the invention. A prodrug,metabolite or derivative of the drug can also be included.

In some embodiments, the salt forms of risperidone can be made accordingto U.S. Publication No. 20040266791, the relevant disclosure of which ishereby incorporated by reference; however, other known salts can beused. Since paliperidone and risperidone share substantial structuralsimilarity, salts of paliperidone can be made as described for salts ofrisperidone.

As used herein, the term “prodrug” is taken to mean a compound that isadministered in an inactive (or less than fully active) form, and issubsequently converted to an active pharmacological agent through normalmetabolic processes. A prodrug serves as a type of ‘precursor’ to theintended drug, e.g. risperidone, paliperidone, or other drug.

As used herein, the term “derivative” is taken to mean a compound thatis obtained by chemical modification of a parent compound such that the“derivative” includes within it almost all or all of the chemicalstructure of the parent (or base) compound. A derivative is a compoundthat is formed from a similar compound or a compound that can beimagined to arise from another compound, if one atom is replaced withanother atom or group of atoms. A derivative is a compound derived orobtained from another and containing essential elements of the parentsubstance. A derivative is a chemical compound that may be produced fromanother compound of similar structure in one or more steps.

As used herein, the term “polymeric solution” is taken to mean the fluidcomposition comprising a combination of the solvent and the polymerdissolved therein. In some embodiments, at least 80%, at least 90%, atleast 95%, at least 99% or all of the polymer is dissolved in thesolvent. If not otherwise specified, the viscosity value of thepolymeric solution or the injectable composition is given in Pa·s units.

The compositions of the invention comprise at least a polymer or polymermatrix, a solvent and a drug.

The composition and kit, used to prepare the composition, are providedwith a polymer or copolymer that is soluble in a solvent, which isnon-toxic and water miscible, to form a liquid polymer solution, inwhich the drug is included. When the implantable compositions areexposed to body fluids or water, the solvent (DMSO) diffuses away fromthe polymer-drug mixture and water diffuses into the mixture where itcoagulates the polymer thereby trapping or encapsulating the drug withinthe polymeric matrix as the composition solidifies into a single implantat the injection site. The release of drug follows the generalcharacteristics for diffusion or dissolution of a drug from within apolymeric matrix. Drug is also released by polymer erosion/degradation.The drug (active ingredient) forms a suspension or dispersion within abiodegradable and biocompatible polymeric solution to form an injectablecomposition that can be administered by way of a syringe (or pump) and aneedle. The composition solidifies inside the body by solvent diffusion,thereby forming the single implant at the site of injection.

The polymer or polymer matrix is preferably a biocompatible andbiodegradable polymer matrix. In order not to cause any severe damage tothe body following administration, the preferred polymers arebiocompatible, non-toxic for the human body, not carcinogenic, and donot induce significant tissue inflammation. The polymers are preferablybiodegradable in order to allow natural degradation by body processes,so that they are readily disposable and do not accumulate in the body.The preferred polymeric matrices in the practice in this invention areselected from end-capped terminal carboxylic poly-lactide andpoly-glycolic acid copolymers, e.g. poly(lactic acid-co-glycolic acid)copolymer (PLGA copolymer), mixed in a ratio ranging from 45:55 to 55:45or 48:52 to 52:48, and preferably of about 50:50, i.e. 50:50±10%, withan average molecular weight in the range of 30-45 and preferably in therange of 30-36 KDa, and an inherent viscosity preferably in the range of0.25-0.31 and more preferably in the range of 0.26-0.29 dl/g±10%. Theexpression “about 50:50” as used in this description, refers to amonomer ratio of lactic to glycolic acid of biocompatible copolymerbased on lactic and glycolic acid as applied in the context of theinvention for a monomer ratio measure with an standard technical error(standard deviation) of ±10%. The commercially available grades of PLGAcopolymer are known to vary slightly in their actual ratio of monomerseven though they may be listed as having a 50:50 monomer ratio. Forexample, a copolymer specified as having a monomer ratio of 50:50 mayactually have a monomer ratio ranging from 45:55 to 55:45 or 48:52 to52:48. Accordingly, whenever the monomer ratio of “50:50” or “about50:50” is specified herein, all ratios ranging from 45:55 to 55:45 areconsidered as being interchangeable therewith.

Inherent viscosity can be measured in chloroform at 25° C. at aconcentration of 0.1% wt/v with a Ubbelhode size 0 c glass capillaryviscometer (RESOMER® grades) or in chloroform at 30° C. and at aconcentration of 0.5% wt/v with a size 25 Cannon-Fenske glass capillaryviscometer (LAKESHORE MATERIALS™ grades). Suitable grades of PLGAcopolymers as described herein (according to molecular weight, intrinsicviscosity and/or molar ratio of lactic acid monomer to glycolic acidmonomer) are end-capped (such as with an ester group, e.g. lauryl ester,methyl ester) are available from EVONIK® (Essen, Germany), BoehringerIngelheim (Ingelheim am Rhein, Germany), ALKERMES (Dublin, Ireland) orSIGMA ALDRICH (ST. Louis, Mo.) and are marketed under the tradenamesRESOMER®, LAKESHORE BIOMATERIALS™, or MEDISORB®. As the composition ofsome grades of end-capped PLGA is proprietary, the identity of the esterend-cap is not publicly available. Nonetheless, the performanceproperties of the grades of PLGA copolymer described herein are knownand are used to characterize the material.

For the purpose of the present invention, throughout the presentspecification the term intrinsic or inherent viscosity (η_(inh)) of thepolymer is defined as the ratio of the natural logarithm of the relativeviscosity, η_(r), to the mass concentration of the polymer, c, i.e.:

η_(inh)=(ln η_(r))/c

and the relative viscosity (η_(r)) is the ratio of the viscosity of thesolution η to the viscosity of the solvent η_(s), i.e.:

η_(r)=η/η_(s)

If not otherwise specified, the intrinsic viscosity and molecular weightvalues throughout the present specification are to be understood asmeasured with the method explained in example 1. The value of intrinsicviscosity is considered in the present specification, as commonlyaccepted in the art, as an indirect indicator of the polymer molecularweight. In this way, a reduction in the intrinsic viscosity of apolymer, measured at a given concentration in a certain solvent, withsame monomer composition and terminal end groups, is an indication of areduction in the polymer molecular weight (IUPAC. Basic definitions ofterms relating to polymers 1974. Pure Appl. Chem. 40, 477-491 (1974).

A commercial polymer with the required molecular weight can certainly beused. However, we have determined that the essential range of itsmolecular weight is between 30-46 and preferably between 30-45 kDa.Additionally we have determined in an in-house custom design that themolecular weight of the polymer can be varied by irradiating it with aradiation dose of between 15 and 30 kGy±10% or even more at atemperature lower than 8° C. and this was not obvious in view of thestate of the art to the skilled person (see FIG. 11). For example, themolecular weight of a commercially available polymer in a certain momentcan be 50 KDa as an average value. We have determined a method forvarying this molecular weight by irradiating the polymer with a certaindose of radiation that can be previously calculated. If done undercontrolled conditions, it is possible to obtain a mathematical modelshowing that the molecular weight of the polymer can be decreased withincreasing irradiation doses. Since, if the molecular weight of thepolymer is adjusted, its inherent viscosity is correspondingly varied,it follows that by irradiating the polymer with certain definedradiation doses we achieve both the adjustment of its molecular weightand its inherent viscosity. For example:

-   -   When a PLGA polymer having a molecular weight between 30 and 46        kDa and an inherent viscosity value in the range of 0.25-0.31        dl/g is needed, and we have as the starting polymer a polymer        with 56 KDa of average molecular weight, we have determined that        a radiation dose of 25 KGy is required to reduce its molecular        weight to the cited range of 30-46 kDa.    -   When a PLGA polymer having a molecular weight between 30 and 40        and preferably between 30 and 36 kDa and an inherent viscosity        value in the range of 0.25-0.31 dl/g and preferably 0.26-0.29        dl/g is needed, and we have as the starting polymer a polymer        with 50 KDa of average molecular weight, we have determined that        a radiation dose of 25 KGy is required to reduce its molecular        weight to the cited range of 30-40 kDa and preferably 36-40 kDa.    -   When a PLGA polymer having a molecular weight between 30 and 40        kDa and an inherent viscosity value in the range of 0.25-0.31        dl/g is needed, and we have as the starting polymer a polymer        with 38 KDa of average molecular weight, we have determined that        there is no need to use any radiation dose.    -   When a PLGA polymer having a molecular weight between 30 and 36        kDa and an inherent viscosity value in the range of 0.25-0.31        and preferably of 0.26-0.29 dl/g is needed, and we have as the        starting polymer a polymer with 38 KDa of average molecular        weight, we have determined that a radiation dose of 16 KGy is        required to reduce its molecular weight to the cited range of        30-36 kDa.    -   When a PLGA polymer having a molecular weight between 30 and 36        kDa and an inherent viscosity value in the range of 0.25-0.31        and preferably of 0.26-0.29 dl/g is needed, and we have as the        starting polymer a polymer with 31 KDa of average molecular        weight, we have determined that there is no need to use any        radiation dose.    -   When a PLGA polymer having a molecular weight between 30 and 46        kDa and an inherent viscosity value in the range of 0.25-0.31        and preferably of 0.26-0.29 dl/g is needed, and we have as the        starting polymer a polymer with 63 KDa of average molecular        weight, we have determined that a radiation dose of 30 KGy is        required to reduce its molecular weight to the cited range of        30-46 kDa and preferably of 30-36 kDa.

In these experimental tests, the temperature conditions for the polymerduring the irradiation were about 8° C. However, other temperatures canbe used, such as e.g. lower than 35° C., or lower than 25° C., althoughin these cases the relationships between the radiation dose and theresulting molecular weight may vary.

The irradiation procedure is especially suitable for the manufacturingof the compositions described herein. Furthermore, the filling of thesolid polymer into syringes generally represents a real challenge in themanufacturing of injectable formulations. The polymer, manufactured as anon-sterile product, requires sterilization in order to be suitable forinjection. We subjected the polymer to sterilization by gamma- orbeta-irradiation. Irradiation represents a challenging issue when usingbiodegradable polymers, as irradiation can disrupt the chains intofractions of smaller size. Control of the polymer molecular weightappears as again as the critical parameter to control the finalcharacteristics of a product after a sterilization process.

Chain size reduction by irradiation can be mathematically modelled orcontrolled in order to predict the final molecular weight of a polymerto be used as raw material having a molecular weight higher thandesired. Therefore, once determined the fill weight of the polymer to befilled in a container (for example, the fill weight of the polymer in asyringe) and the bio-burden present in the polymer as raw material, theirradiation dose required to get the polymer sterile (as specified byISO 11137) is selected for the required fill weight. Then themathematical model describing the loss of molecular weight for a certainpolymer versus the irradiated dose can identify the initial molecularweight of the polymer to be used as raw material required obtaining,after the irradiation process, a polymer with the desired finalmolecular weight for the formulation. As the availability of a polymerwith a specific molecular weight can be somewhat limited, then we canalternatively select an available polymer with a molecular weight thatis higher to what is required according to the irradiation doseidentified, and then adjust the irradiation dose to a higher value inorder to obtain a sterile polymer with the required molecular weight.

The concentration of the polymeric component in the compositions of theinvention is in the range of 24%-50% wt, 24%-40% wt, 24%-30% wt, 25-27%wt or 26% wt, (expressed as the percentage of polymer weight based ontotal composition weight).

The preferred solvents are non-toxic, biocompatible and appropriate forparenteral injection. Solvents susceptible of causing toxicity shouldnot be used for the injection of any material into any living body. Morepreferably, selected solvents are biocompatible in order not to causeany severe tissue irritation or necrosis at the injection site.Therefore, the solvent is preferably classified as class II or III, andmore preferably class III, according to ICH Guidelines. For theformation of the in-situ implant, the solvent should preferably diffusequickly from the polymeric solution towards surrounding tissues when isexposed to physiological fluids. Consequently, the solvent is preferablyDMSO.

The drug is preferably risperidone, and/or paliperidone and allpharmaceutically acceptable salts or combinations thereof. This drug ispreferably at least partly suspended in the solvent. The solubility ofthe drug in the solvent is preferably lower than 90 mg/ml, morepreferably lower than 65 mg/ml, and most preferably below 10 mg/ml. Theadvantage of this low solubility is that the initial burst of the drugwhen the solvent diffuses to the external aqueous medium is greatlyreduced. In addition, in the final compositions of the invention thedrug is provided in a concentration (the drug content) between 4 and 16wt %, expressed as the percentage of the drug with respect to the totalcomposition weight (drug+polymer+solvent). In some embodiments, the drugcontent ranges from about 4% to about 16% wt, about 7% to about 15% wt,about 10% to about 15% wt, about 12% to about 14% wt, or about 13% wt

After administration, the injectable composition forms an implant thatprovides a satisfactorily controlled release profile for the drug. By“satisfactorily controlled” release profile is meant that the implantwill exhibit an initial release profile that is not too steep (fast),which would otherwise lead to plasma levels that are too high withconcomitant toxic side effects, and an initial release profile that isnot too flat (slow), which would lead to plasma levels that are belowtherapeutic concentrations. An implant exhibiting a satisfactorilycontrolled initial release profile will release will release no morethan 20% wt., no more than 15% wt, no more than 12% wt, no more than 10%wt, no more than 8% wt no more than 6% wt, no more than 5% wt, no morethan 4% wt, no more than 3% wt, no more than 2% wt or no more than 1% wtof its charge of drug within 24 hours after being placed in an aqueousenvironment. It will release at least 0.1% wt, at least 0.5% wt., atleast 1% wt, at least 2% wt., at least 3% wt or at least 4% wt of itscharge of drug within 24 hours after being placed in an aqueousenvironment. The invention includes all combinations of the embodimentsherein.

One of the factors contributing to control the initial release of thecomposition of the invention is the viscosity of the polymeric solution.In some embodiments, at least 80%, at least 90%, at least 95%, at least99% or all of the polymer is dissolved in the solvent. If not otherwisespecified, the viscosity value of the polymeric solution or theinjectable composition is given in Pa·s units, measured in chloroform at25° C. and at concentration of 0.1% wt/v. The “polymeric solution”,which is defined as the combination of the polymer and the solvent whereit is dissolved, has a preferred viscosity in the range of 1.5-2.1±10%Pa·s, in the range of 1.6-1.9±10% Pa·s or in the range of 1.7-1.8±10%Pa·s. The viscosity can be controlled primarily according to themolecular weight (the intrinsic or inherent viscosity) of the polymerand the concentration of polymer in the injectable composition.

Another factor contributing to control the initial release of thecompositions of the invention is the biocompatible copolymer molecularweight that must be between 30 and 46 and preferably between 30 and 45kDa. The adequate balance in this composition between drug solubility inthe solvent and the molecular weight of the polymer in the implant (thatcontrols the polymer precipitation process and the final structuralcharacteristics of the implant) allows the formulation to limit theamount of risperidone that can be released in the solvent diffusionphase after the intramuscular injection. Once the formulation isinjected in the intramuscular tissue, the DMSO is rapidly dissolved inthe surrounding aqueous environment. The relative increase of thepolymer concentration in DMSO over the polymer solubility in the solventleads to the formation of a polymer precipitate that entraps therisperidone that was not solubilized in the solvent. Molecular weight ofthe polymer has an impact upon this critical step, as PLGA chains withtoo low a molecular weight exhibit delayed precipitation time comparedto the chains possessing a molecular weight in the required range. Thisdelayed precipitation allows the drug to increase contact with thesurrounding fluids and increases the initial amount or rate of drugrelease. Therefore, low molecular weighed chains lead to an excessiverelease of risperidone after the injection and potentially lead to toxicplasma levels on the first days after the injection. Molecular weight ofthe polymer also can affect the release of the drug from theintramuscularly injected implant after solvent diffusion and polymerprecipitation. Molecular weights over the specified range are notcapable of maintaining adequate release rates of risperidone orpaliperidone by diffusion. Additionally, higher molecular weight chainsin the intramuscular tissue require longer hydrolysis times in order toprovide soluble fractions that could release the drug entrapped in thepolymer matrix. The increased amount of unreleased drug remaining in animplant at the end of a dosing period, e.g. at the end of 28-35 days,might lead to undesirably high active moiety plasma concentrations, orplasma concentrations after 30 days post injection that could somehowinterfere with subsequent doses, given that the formulation is generallyintended for sequential administration every 4 weeks to 30 days.

The invention provides an injectable intramuscular depot compositionsuitable for forming an in situ solid implant in a body, the compositioncomprising: a drug which is risperidone and/or paliperidone or anypharmaceutically acceptable salt thereof in any combination; abiocompatible PLGA copolymer based on lactic and glycolic acid andhaving a monomer ratio of lactic to glycolic acid of ranging from 45:55to 55:45 and preferably about 50:50, i.e. 50:50±10%; and DMSO, whereinthe composition releases the drug with an immediate onset of action andcontinuously for at least 4 weeks, and wherein the composition has apharmacokinetic profile in vivo that makes it suitable foradministration every about 4 weeks or even longer periods characterisedin that the biocompatible copolymer has a molecular weight between 30and 46 kDa, preferably between 30 and 36 kDa, and has an inherentviscosity in the range of 0.25-0.31±10% dl/g or 0.26-0.29±10% dl/g.

In a preferred embodiment of the invention, the biocompatible copolymeris gamma- or beta-irradiated in the dose range of 15-30 KGy and at atemperature higher than −40° C. but lower than 35° C., more preferablylower than 25° C., even more preferably lower than 15° C. and mostpreferably about 8° C., for adjusting its molecular weight and viscosityranges.

Yet another factor that may contribute toward controlling the initialrelease of drug from the implant is the drug's particle size. Largeparticles provide a smaller surface area per weight thereby reducing theinitial release (burst) but the release may be then delayed until thebeginning of the degradation of the polymeric matrix. On the other hand,small particles evoke higher burst levels due to increased surface areaand easier drug diffusion from small particles during implant hardening,followed by continuous drug release levels due to the combination of theprocesses of drug diffusion and implant erosion. Consequently, in apreferred embodiment of the invention a wide particle size distribution,combining large and small particle sizes in different ratios, is used inorder to reduce the initial burst and still maintain a suitable constantdrug release by diffusion of smaller particles during the first phase ofrelease and gradual release of drug from the bigger particles while thepolymer degrades, i.e. during the period of time (days to weeks)following the initial burst phase.

If not otherwise specified, the particle size distribution wasdetermined by light scattering technique using laser light diffractionin wet mode. It is known that particle size distribution results can bealtered as a function of the material treatment such the use of highconcentrate surfactant agents and/or strong force energies (vortex,sonication, etc). If nothing else is mentioned, drug is not treated andsamples are prepared by direct addition to the tank under moderatestirring (2000-3500 rpm). The methodology applied on present inventionto determine the drug particle size distribution mimics in a morefaithfully way the behavior of the drug powder on the injectableformulation herein described than other methods which apply forceenergies to the sample and/or use high concentrate surfactant agents forpreparing the samples in order to achieve high degrees of powderdisaggregation that cannot be simulated during the manual reconstitutionprocess of the formulation.

In some embodiments, the particle size distribution of the drug is asfollows: not more than 10% of the total volume of drug particles areless than 10 microns in size (equivalent diameter in volume as afunction of applying Fraunhofer theory to irregularly shape particles;as measured by laser light scattering, such as with a Malvem Mastersizer2000) and not more than 10% of the total volume of drug particles aregreater than 225 microns in size. In addition, the drug particlespossess a d0.5 value preferably in the range of about 60-130 microns.

In some embodiments, the drug exhibits one of the following particlesize distributions:

Parameter I II III IV V VI d0.1 (microns) 27.49  <30 17.41  ≦20  ≦10 ≦10 d0.5 (microns) 79.90 40-130 51.61 40-130 40-130 40-130 d0.9(microns) 176.66 >170 175.32 >170 >225 >200

In a preferred embodiment of the invention, this drug has the particlesize distribution as follows:

-   -   less than 10% particles smaller than 10 microns;    -   less than 10% particles larger than 225 microns, and    -   a d0.5 value in the range of 40-130 microns.

Additional parameters such as the mass ratio of drug to polymericsolution (polymer+solvent), the mass ratio of drug to (polymer+drug),the mass ratio of solvent/drug, the mass ratio of polymer to polymericsolution (polymer+solvent), the mass ratio of solvent to polymericsolution (polymer+solvent), can also be useful to provide control overthe initial release and/or controlled release of drug from thecompositions of the invention.

In some embodiments, the mass ratio of polymeric solution to drug,expressed as the mass of (polymer+solvent) to the mass drug, ranges fromabout 15:1 to about 5:1, about 12:1 to about 5:1, from about 7:1 toabout 6.5:1, about 6.5:1 to about 6.8:1, about 6.67:1 or about 6.68:1.

In some embodiments, the mass ratio of drug to (polymer+drug), expressedas the percentage of the drug weight with respect to total weight of thedrug plus polymer, is in the range of about 15-40% weight, about 25-35%wt, about 30-35%, about 31-35%, about 32-34% or about 33% wt.

In some embodiments, the mass ratio of solvent to drug is in the rangeof about 12:1 to about 4:1, about 10:1 to about 4:1, about 5:1 to about4:1, about 4.6:1 to about 4.7:1, about 4.67:1, about 4.66:1 or about4.68:1.

In some embodiments, the mass ratio of polymer to polymeric solution,expressed as the weight percentage of polymer with respect to the weightof polymer+solvent, is about 25-50%, about 25-35%, about 30-40%, about28-32%, or about 30%.

In some embodiments, the mass ratio of solvent to polymeric solution,expressed as the weight percentage of solvent with respect to the weightof polymer+solvent, is about 60-80%, about 65-75%, about 67-72%, orabout 70%.

In some embodiments, the drug/polymer+drug mass ratio is about 33%, thecontent of drug is about 13% w/w of total formulation, the viscosity ofthe polymeric solution (PLGA polymer and DMSO) is in the range of about1.5-2.1±10% P·a·s or about 1.7-1.8±10% P·a·s.

In some embodiments, the drug is partially suspended with a solubilityof drug in the DMSO solvent below 10 mg/ml. In some embodiments, thedrug is partially dissolved or substantially completely undissolved inthe solvent, DMSO, polymeric solution or injectable composition. In someembodiments, ≦2.5%, ≦5%, ≦7.5%, ≦10%, ≦20% or ≦25%, of the drug isdissolved in the solvent or polymeric solution to form the injectablecomposition. In some embodiments, >0%, ≧0.5%, ≧1%, ≧5%, ≧10% or ≧15% orup to about 20% wt. of the drug is dissolved in the solvent or polymericsolution to form the injectable composition. All combinations of theseembodiments are contemplated.

According another embodiment, the biocompatible copolymer of thisinvention is gamma- or beta-radiated, preferably in the range of 10-30KGy, more preferably in the range of 15-30 KGy, and most preferablybetween 16-25 KGy±10%.

According to another embodiment, the composition is a sterilecomposition and is suitable for the treatment of schizophrenia orbipolar disorders in the human body.

Another aspect of the invention provides a method for the treatment of adisease, disorder or condition that is therapeutically responsive to arisperidone and/or paliperidone, the method comprising administering anamount of injectable composition, as defined herein, to a subject inneed thereof, wherein the amount of injectable composition comprises adose of drug and the injectable composition continuously providestherapeutically effective plasma levels of drug in the subjectthroughout a dosing period of at least four weeks beginning from the dayof administration.

The injectable composition can also be used to treat a psychotic diseaseor disorder selected from the group consisting of delusional psychosis,psychotic depression, obsessive-compulsion disorder, schizophrenia,bipolar disorder, schizoaffective disorders, non-schizophrenicpsychoses, Asperger's syndrome, Tourette's syndrome,obsessive-compulsion disorder, post-traumatic stress disorder, attentiondeficit hyperactivity disorder, personality disorders, aggression,depression, dementia, intellectual disabilities and behavioraldisturbances in mental retardation and autism, autistic spectrumdisorders, anxiety, eating disorders, nervous anxiety, insomnia,idiopathic dystonia, substance abuse, and any combination thereof. Theinjectable composition can also be used as an antihistaminic for thetreatment of allergic disorders or as a prolactin secretion promoter forbreastfeeding women or for the treatment of prolactin deficiency.

In yet another embodiment, the invention provides a pharmaceutical kitsuitable for the in situ formation of a biodegradable implant in a bodycomprising the composition claimed, wherein the drug and thebiocompatible polymer are contained in a first container, and thesolvent is contained in a second, separate container. Preferably, atleast one of the first and second containers is a syringe, a vial, adevice or a cartridge, either disposable or not and more preferably boththe first and the second containers are disposable syringes. This aspectof the invention is directed to a kit comprising a first container,preferably syringes, vials, devices or cartridges, all of them eitherbeing disposable or not, containing a polymer in solid form, such asPLGA and a drug in the appropriate amounts and a second container,likewise preferably syringes, vials, devices or cartridges, all of thembeing either disposable or not, containing the water-miscible solvent.When required, the contents of both containers are combined, for examplethrough a connector or by using male-female syringes, and mixed eachother so that the compositions according to the invention arereconstituted, for example by moving forwards and backwards the plungersof the syringes. Illustrative preferred embodiments are shown in FIG. 9(syringes connected through a connector device) and in FIG. 10 (syringesconnected through a direct thread).

According to another aspect, the invention provides a method formanufacturing an injectable composition, the method comprising:providing a biocompatible copolymer having a polymer weight higher thanrequired for the intramuscular depot composition; and then reducing itsmolecular weight to between 30 and 46 kDa by irradiating it with gammaor beta radiation in the dose range of 15-30 KGy.

In some embodiments, when the biocompatible polymer has an initialmolecular weight of about 56 kDa, it is irradiated with a radiation doseof about 25 KGy to reduce its molecular weight to between 30 and 46kDa±10%.

In some embodiments, when the biocompatible polymer has an initialmolecular weight of about 50 kDa, it is irradiated with a radiation doseof about 25 KGy to reduce its molecular weight to between 30 and 40 andpreferably between 30 and 36 kDa±10%.

In some embodiments, when the biocompatible polymer has an initialmolecular weight of about 38 kDa, it is irradiated with a radiation doseof about 16 KGy to reduce its molecular weight to between 30 and 36 kDa.

In some embodiments, when the biocompatible polymer has an initialmolecular weight of about 63 kDa, it is irradiated with a radiation doseof about 30 KGy to reduce its molecular weight to between 30 and 46 andpreferably between 30 and 36 kDa±10%.

According another aspect, the invention provides a dosing regimen methodfor administering the injectable intramuscular depot composition to apatient in need of psychiatric treatment comprising:

-   -   a) administering intramuscularly to the patient a first dose in        the amount of 37 mg to 150 mg of the injectable depot        composition; and then,    -   b) administering a subsequent dose of the injectable depot        composition in the amount of 37 mg to 150 mg, at a point of time        between the 24^(th) day and the 35^(th) day counting from the        previous administration day.    -   c) repeating step b) as many times whenever required.

Preferably, the first dose is about 50 mg to about 100 mg and this isequivalent to other subsequent doses.

Within a treatment period, administered doses of injectable compositioncan be the same or different. In some embodiments, a prior dose ishigher or lower than a following dose in a sequence of doses. Two ormore doses administered in a treatment period can be the same ordifferent. In some embodiments, two or more doses administered in atreatment period are the same. In some embodiments, two or more dosesadministered in a treatment period are different. Combinations of theseembodiments are within the scope of the invention.

In a preferred embodiment, the injectable depot composition is sterileas a finished product. In other preferred embodiment, the biocompatiblepolymer is sterilized previously to its aseptic filling process,preferably by irradiation in the range 15-30 KGy or by other processlike filtration.

All values disclosed herein may have standard technical measure error(standard deviation) of ±10%.

Although not required, the present injectable composition can furthercomprise an alkaline agent. An alkaline agent with low water solubilitysuch as lower than 0.02 mg/ml can be included. The alkaline agent can bepresent in a molar ratio >2/5 (drug/alkaline agent), meaning that thealkaline agent is present in molar excess over the drug. Preferredalkaline agents are alkaline or alkaline-earth hydroxides, such asmagnesium hydroxide or aluminum hydroxide. Due to the limited watersolubility of the alkaline agent, the d 0.5 of the particle sizedistribution, e.g. of the magnesium hydroxide, is preferably below 10microns.

It may be necessary to use a starting dosing regimen in order toaccelerate obtaining the desired plasma levels before starting the 4weekly dosing regimen. This starting regimen could be, for example butnot limited to, as is described below:

-   -   A first intramuscular dose of the formulation at day 0, in a        dose between 25 to 200 mg, followed by a second dose between        days 5-10 with a dose in the range of 25 to 200 mg, followed by        a third dose between days 28-35 after the first dose, with a        dose in the range of 25-200 mg, and then subsequent 4 weekly        doses of the formulation;    -   A first intramuscular dose of the formulation at day 0, in a        dose between 75 to 200 mg, followed by a second dose between        days 28-35 with a dose in the range of 25 to 200 mg, and then        subsequent 4 weekly doses of the formulation; or    -   Any other combination of strengths and intervals needed to        obtain the plasma levels needed to start a 4 weekly        administration.

The intramuscular dose can be administered to any muscle or muscle grouptypically recognized by the pharmaceutical industry as a suitable sitefor an injectable composition. In some embodiments, the composition isadministered to the gluteal and/or deltoid muscles. The composition canalso be administered to the quadriceps muscle group.

Administration of a single dose is typically considered that amount ofinjectable composition administered to a subject within a period of upto 24 hours, up to 12 hours, up to 6 hours, up to 3 hours, up to onehour, up to 30 min, up to 15 min or up to 5 min.

A dose of injectable composition refers to an amount of injectablecomposition comprising a specified dose of drug. Accordingly, a dose of25-200 mg of injectable composition comprises a dose of 25-200 mg ofdrug; therefore, the actual amount of injectable compositionadministered would be greater than 25-200 mg, the actual amount ofinjectable composition being determined according to the content drug inthe injectable composition.

A dose can be administered to a single muscular site or can be dividedinto two or more portions and administered to two or more muscular sitesof a subject. For example, a first portion of a dose can be administeredto a first section of gluteal muscle and a second portion of the dosecan be administered to a second section of gluteal muscle of a subject.

As used herein, the term “dosing period” refers to the period of days orweeks as measured from the initial day after administration of a dose toat least 28 days after administration or to administration of asubsequent dose. During the dosing period, the implant will providetherapeutic plasma levels of drug for at least at least 4-5 weeks. Adosing period can end after expiration of a predetermined number of daysor after the plasma level of drug drops below therapeutic levels.

As used herein, a “treatment period” refers to the weeks, months oryears during which implants of the invention are administered to asubject. A treatment period generally comprises plural dosing periods.Dosing periods can occur sequentially or in an overlapping manner duringa treatment period. For example, a first dose of injectable compositionis administered and a second dose of injectable composition can beadministered at a time following administration of the first dose, suchthat each dose will have its own corresponding dosing period, and thedosing periods would overlap. Dosing periods will typically besequential or overlap by no more than one or seven days.

The injectable composition can be administered to a subject in one ormore injection sites on the same day and still be considered as beingpart of the same dosing period. For example, part of a dose can beadministered to a first injection site and another part of the same dosecan be administered to another injection site. A single-body implantwill form at each injection site. Such a mode of administration within asame day is considered to be administration of a single dose with asingle dosing period.

Alternatively, administration can be modified such that there is onepoint of needle entry into the subject but more than one injection sitebelow the skin, which can be achieved by making a first penetration intothe skin and muscle and administering a portion of a dose, thenpartially withdrawing and redirecting the needle into another section ofmuscle, while maintaining the tip of the needle beneath the skin, andthen injecting another portion of the dose into this other section ofmuscle. Such a mode of administration is still considered to beadministration of a single dose within a single dosing period.

The plasma concentration profile during the dosing period can exhibitone, two, or more maxima and one, two or more minima. An initial maximumcan be caused by dissolution of drug during the initial day(s) of thedosing period followed by a slowing of the release thereof and anothermaximum can be caused by increased rate of release during the remainingdays of the dosing period. Embodiments of the invention include thosewherein: a) the plasma profile exhibits a maximum during the initial oneto six days or one to three days of the dosing period; b) the plasmaprofile exhibits a maximum during the latter 14 to 24 days of a 4-weekdosing period; c) the plasma profile exhibits a maximum during theinitial days of the dosing period and a maximum during the remainingdays of the dosing period; d) the plasma profile is substantially level(a standard deviation within ±30%, ±25%, ±20%, ±15%, ±10% or ±5% of theaverage or mean) during the dosing period; e) the plasma profileexhibits a maximum during the initial two to six days or two to twelvedays of the dosing period; and/or f) the plasma profile exhibits amaximum during the latter 14 to 28 days of a 4- to 5-week dosing period.

The implant of the invention can provide substantially improved plasmalevels of drug when compared to another injectable formulation (notaccording to the invention) containing the same drug when administeredon an equivalent dose basis.

As used herein the term, “initial burst” or “initial release” refers tothe addition of the plasma levels of drug plus those of activemetabolite, which addition is also called “the active moiety” throughoutthe present specification, from the moment of injection/administrationof the injectable composition to a subject in need thereof untilcompletion of the third day after the administration. For example, thedrug can be risperidone and its metabolite can be paliperidone. In someembodiments, the initial period of release is within three days, withintwo days, within one day or within twelve hours after administration.

The injectable depot composition of the invention provides an adequateplasma level profile for drug after administration during a dosingperiod. An “adequate plasma level profile” is considered as providingnot more than (NMT) 45% of the AUC of the paliperidone occurring betweenthe moment of the injection until completion of 30% of a dosing period,between 35% and 45% of the AUC of the paliperidone occurring during theperiod of time that is after 30% and up to 70% of a dosing period, andnot more than 35% of the AUC of the paliperidone occurring during theperiod of time that is after 70% of a dosing period. The total AUC isdetermined as the AUC for the entire dosing period.

For an 4-week to 5-week dosing period, an “adequate plasma levelprofile” is considered as not more than (NMT) 45% of the AUC of thepaliperidone occurring between the moment of the injection until day 7(included), between 35% and 45% of the AUC of the paliperidone occurringbetween day 7 and day 21 (included), and not more than 35% of the AUC ofthe paliperidone occurring after day 21 until completion of the dosingperiod. In some embodiments, the injectable depot composition provides aplasma level profile for drug as follows.

Percentage of Drug AUC During the Period Following Administration (day)Form- From day 8 to From Day 22 up to ulation Day-0 up to day 7 day 21day 28 X NMT 45% of AUC 35%-45% of AUC NMT 35% of AUC Y 20%-45% of AUC35%-45% of AUC 10%-35% of AUC Z 30%-45% of AUC 35%-45% of AUC 20%-35% ofAUC

The above percentages represent an adequate balance between thedifferent periods in which paliperidone is being released from theimplant in order to have a formulation to be injected each 4 to 5 weeksor every about 30 days to provide therapeutic plasma levels ofpaliperidone in a human since the first day of the injection and toprovide the desired average paliperidone plasma concentrations duringthe period between injections and with reduced peak-valley plasma valuesof paliperidone that could lead to toxicity or lack of efficacy.

The term “about” is intended to mean ±10%, ±5%, ±2.5% or ±1% relative toa specified value, i.e. “about” 20% means 20±2%, 20±1%, 20±0.5% or20±0.25%.

EXAMPLES

The following examples illustrate the invention and should not beconsidered in a limitative sense thereof.

Acceptable plasma levels of active moiety during the initial burst phaseare below 75 ng/ml in Beagle dogs when doses administered are 2.5 mg/kgrisperidone.

Example 1 Depot Formulation with Resomer® 503 without Radiation

In the present example, the following formulation was prepared:

Ingredient Amount (mg) Female Lactic-co-glycolic acid copolymer 50 2.25ml syringe (N-capped) with 50% content of each of the two organic acidmonomers and a molecular weight of 32 KDa. Risperidone 25 Male Dimethylsulfoxide 117 2.25 ml syringe

Risperidone particle size was characterized by light scattering andprovided the following distribution of particle size: d(0.1)=27.49 μm,d(0.5)=79.90 μm and d(0.9)=176.66 μm.

Polymer has been characterized for its molecular weight according to thefollowing technique:

Equipment

GPC chromatograph with triple detector (laser diffraction, viscosimetry,refraction index)

-   -   Viscotek® GPCmax VE 2001 GPC SOLVENT/SAMPLE MODULE    -   Viscotek® TDA 305 TRIPLE DETECTOR ARRAY

Reagents:

-   -   Tetrahydrofurane (THF) grade GPC stabilized with butyl hydroxyl        toluene (BHT) 250 ppm    -   Polystyrene narrow standard (preferably about a molecular weight        of 90 or 99 KDa)

Sample Preparation:

-   -   1-2 mg/ml Standard Sample    -   10 mg/ml Test sample: 3 samples for each polymer to be tested

Pre-Conditioning:

Condition and stabilize column and detectors with mobile phase (THF)until reaching working flow rate of 1 ml/min and purge viscometer andrefraction index detectors, checking at the end that all signals arestable and adequate.

Chromatographic Conditions:

-   -   Column: 2 serial columns i-MBMMW-3078 (CLM1012, Viscotek)    -   Delay column: medium delay (CLM9002, Viscotek)    -   Column temperature 30° C.    -   Flux rate 1 ml/min    -   Injection volume: 100 μl    -   Run time: 35 minutes    -   Eluent: stabilized THF (pre-heated to 30° C. and under 100 rpm        agitation)

System Verification:

Inject 100 μl of eluent and check there is no response in signalsrelated with molecular weight determination

-   -   Inject 100 μl of polystyrene narrow standard and check adequacy        of the measurement. Repeat at least twice.    -   Acceptance Criteria: ±5% of the nominal Molecular Weight and ±3%        Intrinsic Viscosity declared by manufacturer standard        certificate.

Calibration:

Not necessary if system verification complies and no previouschromatographic conditions are changed.

In case it would be required to calibrate:

-   -   Inject 100 μl of polystyrene standard at least twice.    -   Use first sample's data for triple calibration by creating a new        multidetectors—homopolymer's method.    -   Introduce into the method all the data needed for internal        calibration such standard values of MW, IV, do/dc, dA/dc and        refractive index of the solvent.    -   Calibrate the system as the equipment specify and save the new        method.    -   Check with the new method the adequacy of the measurement for        the second injection of the standard.

Procedure:

Inject by triplicate 100 μl of the test sample

Polymer molecular weight measured according to the technique specifiedresulted in 32 KDa. According to a similar technique, inherent viscosityof the polymer resulted in a value of 0.27 dl/g. It is important tomention that inherent viscosity values correspond to those obtained withthe technique described, specially related to temperature conditions andeluent used. Any change in measurement conditions mean the obtention ofdifferent values as directly depend on them.

The risperidone implantable formulation was prepared by connecting maleand female syringes and moving the plungers forwards and backwards uponcomplete dissolution of the polymer and the formation of a homogeneoussuspension of the risperidone in the polymer dissolution.

In Vivo Plasma Levels after Intramuscular Administration to Beagle Dog:

The risperidone composition of this example was intramuscularly injectedto Beagle dogs weighing an average of 10 kg. The amount injectedcorresponded to a dose of 25 mg risperidone and the composition wasintramuscularly placed in the left hind leg using a syringe with a 20 Gneedle. Total number of dogs was 3. After injection, plasma levels wereobtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 15 d, 17 d, 21 d, 24d, 28 d, 30 d, 35 d, 37 d and 42 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of theplasma levels of the risperidone active moiety and the AUC valuescalculated are shown in FIG. 1. The results are expressed as theaddition of risperidone plus 9-OH-risperidone concentrations (ng/ml) asthe function of time, since the therapeutic activity of 9-OH-risperidoneis substantially equivalent to that of risperidone.

As it can be observed in this Figure, the injection of an amount ofcomposition equivalent to 25 mg risperidone to Beagle dogs resulted invery high control of the initial burst release followed by a slow,sustained decrease, with continuous plasma levels from day 1 onwards.

The plasma levels profile for the active moiety, as previouslydescribed, can be considered adequate as provide very low risk of havingtoxic plasma levels just after the injection. The adequate balance inthis composition between drug solubility in the solvent and themolecular weight of the polymer in the implant (that controls thepolymer precipitation process and the final structural characteristicsof the implant) allows the formulation to limit the amount ofrisperidone that can be released in the solvent diffusion phase afterthe intramuscular injection.

Once the formulation is injected in the intramuscular tissue, the DMSOis rapidly dissolved in the surrounding aqueous environment. Therelative increase of the polymer concentration in DMSO over the polymersolubility in the solvent leads to the formation of a polymerprecipitate that entraps the risperidone that was not solubilized in thesolvent. Molecular weight of the polymer has a great impact in thiscritical step, as too low weighed chains have delayed precipitation timecompared to the chains having the weight in the adequate range. Thisdelayed precipitation allows the drug to increase contact with thesurrounding fluids towards the drug is being released. Therefore, lowmolecular weighed chains lead to an excessive release of risperidoneafter the injection and potentially to obtain toxic plasma levels on thefirst days after the injection. Molecular weight of the polymer also canaffect the release of the drug from the intramuscularly injected implantafter solvent diffusion and polymer precipitation.

Molecular weights over the specified range are not capable to maintainadequate release rates of risperidone by diffusion. Additionally, highermolecular weight chains in the intramuscular tissue require longerhydrolysis times in order to provide soluble fractions that couldrelease the drug entrapped in the polymer matrix. A higher remainingdrug content to be released could lead to the obtention of undesirablyhigh active moiety plasma values, or plasma values after 30 days postinjection that could somehow interfere with the following dose as theformulation is intended to be injected several times into the human,each 4 weeks or 30 days.

The FIG. 1 shows how a polymer in the 30-36 KDa region (32 KDa) iscapable to provide desirable in vivo plasma levels profile.

AUC all AUC₀₋₇ days AUC₇₋₂₁ days AUC_(21-last) (h * ng/ml) (h * ng/ml)(h * ng/ml) (h * ng/ml) Dose 20259.70 7039.78 8657.52 4562.40 2.5 mg/kg

Example 2 Depot Formulation with Resomer® 504 Radiated to 16 KGy

The present example shows how the polymer molecular weight can becontrolled in order to have a sterile formulation with the desired invivo release properties.

Filling solid polymer in syringes represents a real challenge in themanufacturing of injectable formulations. The polymer, manufactured as anon-sterile product, requires undergoing sterilization in order toachieve a formulation that can be injected into human beings. Probablythe best way to solve this technical issue is to subject the polymer tosterilization by gamma or beta irradiation. Irradiation represents achallenging issue when used biodegradable polymers, as irradiation candisrupt the chains into fractions of smaller size. Control of thepolymer molecular weight appears as again as the critical parameter tocontrol the final characteristics of a product after a sterilizationprocess.

However, chain size reduction by irradiation can be mathematicallymodelled or controlled in order to predict the final molecular weight ofa polymer to be used as raw material having a molecular weight higherthan desired. Therefore, once determined the fill weight of the polymerto be filled in a container (for example, the fill weight of the polymerin a syringe) and the bio-burden present in the polymer as raw material,the irradiation dose required to get the polymer sterile (as specifiedby ISO 11137) is selected for the required fill weight.

Then the mathematical model describing the loss of molecular weight fora certain polymer versus the irradiated dose can identify the initialmolecular weight of the polymer to be used as raw material requiredobtaining, after the irradiation process, a polymer with the desiredfinal molecular weight for the formulation.

As the availability of a polymer with a specific molecular weight can besomewhat limited, then we can alternatively select an available polymerwith a molecular weight that is higher to what is required according tothe irradiation dose identified, and then adjust the irradiation dose toa higher value in order to obtain a sterile polymer with the requiredmolecular weight. In this example, a lactic-co-glycolic acid copolymerwith 50% content of each of the two organic acid monomers and amolecular weight of 38 KDa was sterilized by beta irradiation at 16 KGyunder controlled temperature and moisture conditions. The resultantpolymer was characterized for its molecular weight according to themethod described in example 1. Molecular weight after irradiationprocess was 31 KDa.

Amount Ingredient (mg) Female 2.25 ml Lactic-co-glycolic acid copolymer(N-capped) 50 syringe with 50% content of each of the two organic acidmonomers and a molecular weight of 38 KDa, beta-irradiated as a bulkwith a 16 KGy dose achieving a final molecular weight of 31 KDa.Risperidone 25 Male 2.25 ml Dimethyl sulfoxide 117 syringe

Risperidone particle size was characterized by light scattering andprovided the following distribution of particle size: d(0.1)=27.49 μm,d(0.5)=79.90 μm and d(0.9)=176.66 μm.

Inherent viscosity of the irradiated polymer, as calculated by thetechnique described in example 1 was 0.27 dl/g.

The risperidone implantable formulation was prepared by connecting maleand female syringes and moving the plungers forwards and backwards uponcomplete dissolution of the polymer and the formation of a homogeneoussuspension of the risperidone in the polymer dissolution.

In Vivo Plasma Levels after Intramuscular Administration to Beagle Dog:

The risperidone composition of this example was intramuscularly injectedto Beagle dogs weighing an average of 10 kg. Two cohorts were studied attwo different doses: 2.5 mg/kg and 5.0 mg/kg. The composition wasintramuscularly placed in the left hind leg using a syringe with a 20 Gneedle. Total number of dogs on each cohort was 6. After injection,plasma levels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14d, 17 d, 21 d, 24 d, 28 d, 30 d, 32 d, 35 d, 38 d, 42 d, 45 d, 49 d, 52d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of theplasma levels of the risperidone active moiety and the AUC valuescalculated are shown in FIG. 2. The results are expressed as theaddition of risperidone plus 9-OH-risperidone concentrations (ng/ml) asthe function of time, since the therapeutic activity of 9-OH-risperidoneis substantially equivalent to that of risperidone. As it can beobserved in this Figure, the injection of an amount of compositionequivalent to 2.5 mg/kg and 5.0 mg/kg risperidone to Beagle dogsresulted again in very high control of the initial burst releasefollowed by a slow, sustained decrease, with continuous plasma levelsfrom day 1 onwards.

The FIG. 2 shows how a polymer with higher molecular weight can beadjusted to a desired molecular weight and maintain the releasecharacteristics obtained with a non-irradiated polymer with the originalmolecular weight in the range of 30-36 KDa, even though small variationsin the terminal end groups of the polymer chains can occur afterradiation. Again, the plasma levels profile for the active moiety, aspreviously described, can be considered adequate as provide very lowrisk of having toxic plasma levels just after the injection.

AUC all AUC₀₋₇ days AUC₇₋₂₁ days AUC_(21-last) (h * ng/ml) (h * ng/ml)(h * ng/ml) (h * ng/ml) Dose 17537.68 4848.8 6494.76 6194.52 2.5 mg/kgDose 46924.94 9918.74 17170.8 19835.4 5 mg/kg

Example 3 Depot Formulation with Resomer® 504 Radiated to 25 KGy

This is another example that shows how the polymer molecular weight canbe controlled in order to have a sterile formulation with the desired invivo release properties.

A lactic-co-glycolic acid copolymer with 50% content of each of the twoorganic acid monomers and a molecular weight of 50 KDa was sterilized bybeta irradiation at 25 KGy under controlled temperature and moistureconditions. The resultant polymer was characterized for its molecularweight according to the method described in example 1. Molecular weightafter irradiation process was 35 KDa.

Amount Ingredient (mg) Female 2.25 ml Lactic-co-glycolic acid copolymer(N-capped) 50 syringe with 50% content of each of the two organic acidmonomers and a molecular weight of 50 KDa, beta-irradiated as a bulkwith a 25 KGy dose achieving a final molecular weight of 35 KDa.Risperidone 25 Male 2.25 ml Dimethyl sulfoxide 117 syringe

Risperidone particle size was characterized by light scattering andprovided the following distribution of particle size: d(0.1)=27.49 μm,d(0.5)=79.90 μm and d(0.9)=176.66 μm.

Inherent viscosity of the irradiated polymer, as calculated by thetechnique described in example 1 was 0.28 dl/g.

The risperidone implantable formulation was prepared by connecting maleand female syringes and moving the plungers forwards and backwards uponcomplete dissolution of the polymer and the formation of a homogeneoussuspension of the risperidone in the polymer dissolution.

In Vivo Plasma Levels after Intramuscular Administration to Beagle Dog:

The risperidone composition of this example was intramuscularly injectedto Beagle dogs weighing an average of 10 kg. An amount of formulationequivalent to a dose of 2.5 mg/kg of risperidone was intramuscularlyplaced in the left hind leg using a syringe with a 20 G needle. Totalnumber of dogs was 3 After injection, plasma levels were obtained at 0,4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17 d, 21 d, 24 d, 28 d, 30 d,32 d, 35 d, 38 d, 42 d, 45 d, 49 d, 52 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of theplasma levels of the risperidone active moiety and the AUC valuescalculated are shown in FIG. 3. The results are expressed as theaddition of risperidone plus 9-OH-risperidone concentrations (ng/ml) asthe function of time, since the therapeutic activity of 9-OH-risperidoneis substantially equivalent to that of risperidone. As it can beobserved in this FIG. 3, the injection of an amount of compositionequivalent to 2.5 mg/kg to Beagle dogs resulted again in very highcontrol of the initial burst release followed by a slow, sustaineddecrease, with continuous plasma levels from day 1 onwards. Once again,the plasma levels profile for the active moiety, as previouslydescribed, can be considered adequate as provide very low risk of havingtoxic plasma levels just after the injection.

AUC all AUC₀₋₇ days AUC₇₋₂₁ days AUC_(21-last) (h * ng/ml) (h * ng/ml)(h * ng/ml) (h * ng/ml) Dose 17734.84 5134 6844.08 5756.76 2.5 mg/kg

Example 4 Depot Formulation with Lakeshore Biomaterials® 5050 DLG 5ERadiated to 25 KGy

This is another example that shows how the polymer molecular weight canbe controlled in order to have a sterile formulation with the desired invivo release properties.

A lactic-co-glycolic acid copolymer with 50% content of each of the twoorganic acid monomers and a molecular weight of 56 KDa was sterilized bybeta irradiation at 25 KGy under controlled temperature and moistureconditions. The resultant polymer was characterized for its molecularweight according to the method described in example 1. Molecular weightafter irradiation process was 45 KDa.

Amount Ingredient (mg) Female Lactic-co-glycolic acid copolymer(N-capped) 50 2.25 ml with 50% content of each of the two organic acidsyringe monomers and a molecular weight of 56 KDa, beta-irradiated as abulk with a 25 KGy dose achieving a final molecular weight of 45 KDa.Risperidone 25 Male Dimethyl sulfoxide 117 2.25 ml syringe

Risperidone particle size was characterized by light scattering andprovided the following distribution of particle size: d(0.1)=27.49 μm,d(0.5)=79.90 μm and d(0.9)=176.66 μm.

Inherent viscosity of the irradiated polymer, as calculated by thetechnique described in example 1 was 0.28 dl/g.

The risperidone implantable formulation was prepared by connecting maleand female syringes and moving the plungers forwards and backwards uponcomplete dissolution of the polymer and the formation of a homogeneoussuspension of the risperidone in the polymer dissolution.

In Vivo Plasma Levels after Intramuscular Administration to White NewZealand Rabbits

The risperidone composition of this example was intramuscularly injectedto White New Zealand rabbits weighing an average of 3 kg. An amount offormulation equivalent to a dose of 5 mg/kg of risperidone wasintramuscularly placed in the left hind leg using a syringe with a 20 Gneedle. Total number of rabbits was 3. After injection, plasma levelswere obtained at 0, 4 h, 1 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17 d, 21 d, 24d, 28 d, 31 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of theplasma levels of the risperidone active moiety and the AUC valuescalculated are shown in FIG. 4. The results are expressed as theaddition of risperidone plus 9-OH-risperidone concentrations (ng/ml) asthe function of time, since the therapeutic activity of 9-OH-risperidoneis substantially equivalent to that of risperidone. As it can beobserved in this FIG. 4, the injection of an amount of compositionequivalent to 5 mg/kg to White New Zealand rabbits resulted again inhigh control of the initial burst release followed by a slow, sustaineddecrease, with continuous plasma levels from day 1 onwards. Once again,the plasma levels profile for the active moiety, as previouslydescribed, can be considered adequate as provide very low risk of havingtoxic plasma levels just after the injection.

In this example, in which rabbits were used as experimental modelinstead of dogs, it is not applicable the same consideration as an“adequate plasma level profile” than in Beagle dog. Rabbits exhibit ahigher body temperature than Beagle dogs, about 40° C. instead of about37-38° C. Rabbit model shows and accelerated implant degradation, and inconsequence an accelerated risperidone release profile, in comparison todog and human because that higher body temperature promotes a fasterpolymer degradation. This accelerated degradation of polymer does notaffect the first stage of drug release profile during which implant isnot degrading yet, but it leads to a faster second stage during drug isreleased by diffusion and degradation and it leadsd to a consequentlyshorter duration term. For that reason, in case of White New Zealandrabbit, an “adequate plasma level profile” is considered as not morethan the 35% of the AUC of the active moiety (risperidone+9-OHrisperidone plasma concentrations) occurring between the moment of theinjection until day 7 (included), between 35% and 55% of the AUC of theactive moiety occurring from day 7 and until 17 (included), and not morethan 35% of the AUC of the active moiety occurring after day 17.

AUC all AUC₀₋₇ days AUC₇₋₁₇ days AUC_(17-last) (h * ng/ml) (h * ng/ml)(h * ng/ml) (h * ng/ml) Dose 122924.61 4162.63 6521.64 2240.34 5 mg/kg

Example 5 Depot Formulation with Resomer® 504 Radiated to 25 KGy

In this example, a lactic-co-glycolic acid copolymer with 50% content ofeach of the two organic acid monomers and a molecular weight of 38 KDawas sterilized by beta irradiation at 25 KGy under controlledtemperature and moisture conditions. The resultant polymer wascharacterized for its molecular weight according to the method describedin example 1. Molecular weight after irradiation process was 28 KDa.

Amount Ingredient (mg) Female Lactic-co-glycolic acid copolymer(N-capped) with 50 2.25 ml 50% content of each of the two organic acidsyringe monomers and a molecular weight of 38 KDa, beta-irradiated as abulk with a 25 KGy dose achieving a final molecular weight of 28 KDa.Risperidone 25 Male Dimethyl sulfoxide. 117 2.25 ml syringe

Risperidone particle size was characterized by light scattering andprovided the following distribution of particle size: d(0.1)=27.49 μm,d(0.5)=79.90 μm and d(0.9)=176.66 μm.

Inherent viscosity of the irradiated polymer, as calculated by thetechnique described in example 1 was 0.25 dl/g.

The risperidone implantable formulation was prepared by connecting maleand female syringes and moving the plungers forwards and backwards uponcomplete dissolution of the polymer and the formation of a homogeneoussuspension of the risperidone in the polymer dissolution.

In Vivo Plasma Levels after Intramuscular Administration to Beagle Dog:

The risperidone composition of this example was intramuscularly injectedto Beagle dogs weighing an average of 10 kg. An amount of formulationequivalent to a dose of 2.5 mg/kg of risperidone was intramuscularlyplaced in the left hind leg using a syringe with a 20 G needle. Totalnumber of dogs per cohort was 3. After injection, plasma levels wereobtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17 d, 21 d, 24d, and 28 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of theplasma levels of the risperidone active moiety and the AUC valuescalculated are shown in FIG. 5. The results are expressed as theaddition of risperidone plus 9-OH-risperidone concentrations (ng/ml) asthe function of time, since the therapeutic activity of 9-OH-risperidoneis substantially equivalent to that of risperidone. As it can beobserved in this FIG. 5, the injection of an amount of compositionequivalent to 2.5 mg/kg to Beagle dogs resulted in a plasma valuesprofile that is different to the previous formulations tested. Thefigure shows how the formulation provides higher active moiety plasmavalues, probably due to a reduced control of the polymer on the releaseof the drug once the formulation has been injected. A reduced molecularweight could also lead to increased uptake of water throughout the time,leading to greater release of the risperidone by diffusion and to areduced time in which the polymer hydrolizes into smaller sized solublefractions. It is noticeable to mention that this different polymerbehaviour could be obtained with a polymer with a molecular weight only3 KDa less compared to example 2.

AUC all AUC₀₋₇ days AUC₇₋₂₁ days AUC_(21-last) (h * ng/ml) (h * ng/ml)(h * ng/ml) (h * ng/ml) Dose 21702.82 10021.78 9662.28 2018.76 2.5 mg/kg

Example 6 Depot Formulation with Resomer® 503 Radiated to 15 KGy

In this example, a lactic-co-glycolic acid copolymer with 50% content ofeach of the two organic acid monomers and a molecular weight of 32 KDawas sterilized by beta irradiation at 15 KGy under controlledtemperature and moisture conditions. The resultant polymer wascharacterized for its molecular weight according to the method describedin example 1. Molecular weight after irradiation process was 28.3 KDa.

Amount Ingredient (mg) Female Lactic-co-glycolic acid copolymer(N-capped) with 50 2.25 ml 50% content of each of the two organic acidsyringe monomers and a molecular weight of 32 KDa, beta-irradiated as abulk with a 15 KGy dose achieving a final molecular weight of 28.3 KDa.Risperidone 25 Male Dimethyl sulfoxide 117 2.25 ml syringe

Risperidone particle size was characterized by light scattering andprovided the following distribution of particle size: d(0.1)=27.49 μm,d(0.5)=79.90 μm and d(0.9)=176.66 μm.

Inherent viscosity of the irradiated polymer, as calculated by thetechnique described in example 1 was 0.25 dl/g.

The risperidone implantable formulation was prepared by connecting maleand female syringes and moving the plungers forwards and backwards uponcomplete dissolution of the polymer and the formation of a homogeneoussuspension of the risperidone in the polymer dissolution.

In Vivo Plasma Levels after Intramuscular Administration to Beagle Dog:

The risperidone composition of this example was intramuscularly injectedto Beagle dogs weighing an average of 12.5 kg. An amount of formulationequivalent to a dose of 25 mg of risperidone was intramuscularly placedin the left hind leg using a syringe with a 20 G needle. Total number ofdogs per cohort was 3. After injection, plasma levels were obtained at0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17 d, 21 d, 24 d, and 28 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of theplasma levels of the risperidone active moiety and the AUC valuescalculated are shown in FIG. 6. The results are expressed as theaddition of risperidone plus 9-OH-risperidone concentrations (ng/ml) asthe function of time, since the therapeutic activity of 9-OH-risperidoneis substantially equivalent to that of risperidone. As it can beobserved in this Figure, the result was similar to what it was obtainedin example 5. This time, the reduction of molecular weight from theoriginal is only 3.7 KDa, smaller to that observed in examples 2, 3 and4. This is important to notice, as it could had been thought that themore irregular plasma levels profile obtained in example 5 was mostlydue to an intense reduction in the polymer molecular weight, potentiallyleading to an increased heterogeneity in the distribution of thedifferent sized chains. This example shows how the molecule can betailored to a specific molecular weight distribution and to obtainsimilar plasma levels profile.

AUC₇₋₂₁ AUC all AUC₀₋₇ days days AUC_(21-last) (h * ng/ml) (h * ng/ml)(h * ng/ml) (h * ng/ml) Dose 2 mg/kg 13245.14 6873.74 5371.44 999.96

Example 7 Depot Formulation with Resomer® 504 without Radiation

Ingredient Amount (mg) In this example, a lactic- Lactic-co-glycolicacid copolymer (N-capped) with 50 co-glycolic acid copolymer 50% contentof each of the two organic acid with 50% content of each monomers and amolecular weight of 48 KDa. of the two organic acid Risperidone 25monomers and a molecular weight (according to method described inexample 1) of 48 KDa was used. Female 2.25 ml syringe Male 2.25 mlsyringe Dimethyl sulfoxide 117

Risperidone particle size was characterized by light scattering andprovided the following distribution of particle size: d(0.1)=27.49 μm,d(0.5)=79.90 μm and d(0.9)=176.66 μm.

Inherent viscosity of the irradiated polymer, as calculated by thetechnique described in example 1 was 0.33 dl/g.

The risperidone implantable formulation was prepared by connecting maleand female syringes and moving the plungers forwards and backwards uponcomplete dissolution of the polymer and the formation of a homogeneoussuspension of the risperidone in the polymer dissolution.

In Vivo Plasma Levels after Intramuscular Administration to Beagle Dog:

The risperidone composition of this example was intramuscularly injectedto Beagle dogs weighing an average of 12.5 kg. An amount of formulationequivalent to a dose of 25 mg of risperidone was intramuscularly placedin the left hind leg using a syringe with a 20 G needle. Total number ofdogs per cohort was 3. After injection, plasma levels were obtained at0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17 d, 21 d, 24 d, and 28 d.

The kinetics of the plasma levels corresponding to the risperidoneactive moiety was evaluated by measuring both risperidone and its activemetabolite 9-OH-risperidone in the plasma samples. The profile of theplasma levels of the risperidone active moiety and the AUC valuescalculated are shown in FIG. 7. The results are expressed as theaddition of risperidone plus 9-OH-risperidone concentrations (ng/ml) asthe function of time, since the therapeutic activity of 9-OH-risperidoneis substantially equivalent to that of risperidone. The figure shows theeffect of using a polymer with a molecular weight that is higher thanthe range valid for this formulation. Initial plasma values do notchange in a significant way, as risperidone solubility in the DMSO andDMSO diffusion towards surrounding liquids are the major factorscontrolling the release of risperidone from the implant. Then, it can beseen how a reduced release by diffusion leads to a reduction in plasmalevels of active moiety. The higher molecular weight chains of thepolymer also increases the time required to release the risperidone bythe formation of reduced molecular weight soluble polymer molecules byhydrolysis. This fact is detected in the active moiety plasma levelsprofile as a delayed peak.

AUC₇₋₂₁ AUC all AUC₀₋₇ days days AUC_(21-last) (h * ng/ml) (h * ng/ml)(h * ng/ml) (h * ng/ml) Dose 2 mg/kg 15601.88 2902.28 2935.32 9764.28

Example 8 Depot Formulation with Resomer® 504 Radiated to 25 KGy

The current example demonstrates the concept is also valid to achieve anintramuscularly injectable paliperidone formulation suitable to beadministered once each 4 weeks.

A lactic-co-glycolic acid copolymer with 50% content of each of the twoorganic acid monomers and a molecular weight of 50 KDa was sterilized bybeta irradiation at 25 KGy under controlled temperature and moistureconditions. The resultant polymer was characterized for its molecularweight according to the method described in example 1. Molecular weightafter irradiation process was 35 KDa.

Amount Ingredient (mg) Female Lactic-co-glycolic acid copolymer(N-capped) 50 2.25 ml with 50% content of each of the two organic acidsyringe monomers and a molecular weight of 50 KDa, beta-irradiated as abulk with a 25 KGy dose achieving a final molecular weight of 35 KDa.Paliperidone 25 Dimethyl sulfoxide 117

Paliperidone particle size was characterized by light scattering andprovided the following distribution of particle size: d(0.1)=17.41 μm,d(0.5)=51.61 μm and d(0.9)=175.32 μm.

Inherent viscosity of the irradiated polymer, as calculated by thetechnique described in example 1 was 0.28 dl/g.

The paliperidone implantable formulation was prepared by connecting maleand female syringes and moving the plungers forwards and backwards uponcomplete dissolution of the polymer and the formation of a homogeneoussuspension of the paliperidone in the polymer dissolution.

In Vivo Plasma Levels after Intramuscular Administration to Beagle Dog:

The paliperidone composition of this example was intramuscularlyinjected to Beagle dogs weighing an average of 10 kg. An amount offormulation equivalent to a dose of 1.5 mg/kg of risperidone wasintramuscularly placed in the left hind leg using a syringe with a 20 Gneedle. Total number of dogs per cohort was 3. After injection, plasmalevels were obtained at 0, 4 h, 1 d, 2 d, 3 d, 5 d, 7 d, 10 d, 14 d, 17d, 21 d, 24 d, 28 d, 31 d, 35 d, 38 d, 42 d, 45 d, 49 d, 52 d, 56 d, 59d, 63 d, 70 d, 77 d.

The kinetics of the plasma levels corresponding to the paliperidone wasevaluated and the AUC values calculated are shown in FIG. 8. The resultsare expressed as paliperidone concentrations (ng/ml) as the function oftime. As it can be observed in this Figure, the injection of an amountof composition equivalent to 1.5 mg/kg to Beagle dogs resulted again invery high control of the initial burst release followed by a continuouspaliperidone plasma level profile during 59 days. The difference in therelease properties compared to the same risperidone formulation can berelated to different pKa values of both drugs that can affect the invivo biodegradation properties of the polymer and produce release of thedrug over a longer period of time. The formulation tested demonstratesthe feasibility of the composition to obtain a paliperidone formulationthat can provide prolonged release of paliperidone during an entiremonth and can be administered each 4 weeks or even each longer times.

AUC₇₋₂₁ AUC_(21-last) AUC all AUC₀₋₇ days days (h * ng/ (h * ng/ml) (h *ng/ml) (h * ng/ml) ml) Dose 1.5 mg/kg 8636.94 1160.34 3630.84 3845.76

1. An injectable intramuscular depot composition suitable for forming an in situ solid implant in a body, comprising a drug which is risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination, a biocompatible copolymer based on lactic and glycolic acid having a monomer ratio of lactic to glycolic acid of from 45:55 to 55:45 and DMSO as solvent, wherein the composition releases the drug with an immediate onset of action and continuously for at least 4 weeks and wherein the composition has a pharmacokinetic profile in vivo that makes it suitable to be administered each 4 weeks or even longer periods characterised in that the biocompatible copolymer has a molecular weight in the range of between 30 and 46 kDa and an inherent viscosity in the range of between 0.25-0.31±10% dl/g.
 2. The composition of claim 1, wherein the biocompatible copolymer is gamma or beta irradiated in the dose range of 10-30 KGy measured at a temperature between −40° C. and +35° C. to adjust its molecular weight to a range between 30 and 46 kDa and its inherent viscosity to a range of between 0.25-0.31±10% dl/g.
 3. The composition of claim 1, wherein the particle size distribution of the drug is characterized as follows: less than 10% particles smaller than 10 microns; less than 10% particles larger than 225 microns, and a d0.5 value in the range of 40-130 microns.
 4. The composition of claim 1, wherein the drug/(polymer+drug) mass ratio is about 33%.
 5. The composition of claim 1, wherein the content of drug is about 13% w/w of total formulation and the viscosity of the solution comprising the polymer and the DMSO is in the range of 1.5-2.1±10% P·a·s.
 6. (canceled)
 7. A pharmaceutical kit suitable for the in situ formation of a biodegradable implant in a body comprising the composition of claim 1, wherein the drug and the biocompatible polymer are contained in a first container, and the solvent is contained in a second, separate container.
 8. The pharmaceutical kit according to claim 7, wherein at least one of the first and second containers is a syringe, a vial, a device or a cartridge, either disposable or not.
 9. A method for the manufacturing of a composition according to claim 1, comprising the step of providing a biocompatible copolymer having an initial polymer weight higher than required for the intramuscular depot composition and then adjusting its molecular weight to between 30 and 46 kDa and its inherent viscosity to a range of 0.25-0.31 dl/g by irradiating it with gamma or beta radiation in the dose range of 10-30 KGy measured at a temperature between −40° C. and +35° C.
 10. Method according to claim 9 wherein the dose range irradiated to the polymer is in the range of 16 to 25 KGy, measured at 8° C.
 11. The method of claim 9, wherein: a) when the biocompatible polymer has an initial molecular weight of about 56 kDa, it is irradiated with a radiation dose of about 25 KGy to reduce its molecular weight to between 30 and 46 kDa; b) when the biocompatible polymer has an initial molecular weight of about 50 kDa, it is irradiated with a radiation dose of about 25 KGy to reduce its molecular weight to between 30 and 40 kDa; c) when the biocompatible polymer has an initial molecular weight of about 38 kDa, it is irradiated with a radiation dose of about 16 KGy to reduce its molecular weight to between 30 and 36 kDa; or d) when the biocompatible polymer has an initial molecular weight of about 63 kDa, it is irradiated with a radiation dose of about 30 KGy to reduce its molecular weight to between 30 and 46 kDa.
 12. (canceled)
 13. (canceled)
 14. (canceled)
 15. A method for administering an injectable intramuscular depot composition according to claim 1 to a subject in need of psychiatric treatment comprising: administering intramuscularly to the subject a first dose in the amount of 37 mg to 150 mg of the injectable depot composition; and then, administering a subsequent dose of the injectable depot composition in the amount of 37 mg to 150 mg, at a point of time between the 24^(th) day and the 35^(th) day counting from the previous administration day; and repeating step b) as required.
 16. The method of previous claim 15, wherein said first dose is about 50 mg to about 100 mg.
 17. A method of administering paliperidone and/or risperidone to a subject in need thereof, the method comprising: a) administering intramuscularly to the subject doses of sustained release injectable depot composition comprising about 37 mg to about 150 mg of risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination at about 24-day to about 35-day.
 18. The method of claim 17 comprising: a) administering intramuscularly to the subject a dose of sustained release injectable depot composition comprising about 37 mg to about 150 mg of risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination; b) after about 24 to about 35 days or about 4 weeks from the prior dose, administering intramuscularly a dose of sustained release injectable depot composition comprising about 37 mg to about 150 mg of risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination.
 19. (canceled)
 20. A method of administering paliperidone and/or risperidone to a subject in need thereof, the method comprising: a) administering intramuscularly a first dose of sustained release injectable depot composition comprising about 25 mg to about 200 mg of risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination; b) after about 5 to about 10 days from administration of the first dose, administering intramuscularly a second dose of sustained release injectable depot composition comprising about 25 mg to about 200 mg of risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination; c) after about 28 to about 35 days from administration of the first dose, administering intramuscularly a third dose of sustained release injectable depot composition comprising about 25 mg to about 200 mg of risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination; and d) after about 4 weeks from administration of the third dose, administering intramuscularly a dose of sustained release injectable depot composition comprising about 25 mg to about 200 mg of paliperidone.
 21. (canceled)
 22. A method of administering paliperidone and/or risperidone to a subject in need thereof, the method comprising: a) administering intramuscularly a first dose of sustained release injectable depot composition comprising about 75 mg to about 200 mg of risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination; b) after about 28 to about 35 days from administration of the first dose, administering intramuscularly a second dose of sustained release injectable depot composition comprising about 25 mg to about 200 mg of risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination; c) after about 4 weeks from administration of the prior dose, administering intramuscularly a third dose of sustained release injectable depot composition comprising about 25 mg to about 200 mg of risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination.
 23. A method of treating a disease or disorder that is therapeutically responsive to risperidone and/or paliperidone, the method comprising: a) administering risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination according to claim
 17. 24. A method of treating a disease or disorder that is therapeutically responsive to risperidone and/or paliperidone, the method comprising: a) administering risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination according to claim
 18. 25. (canceled)
 26. A method of treating a disease or disorder that is therapeutically responsive to risperidone and/or paliperidone, the method comprising: a) administering risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination according to claim
 20. 27. (canceled)
 28. A method of treating a disease or disorder that is therapeutically responsive to risperidone and/or paliperidone, the method comprising: a) administering risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination according to claim
 22. 29. (canceled)
 30. (canceled)
 31. (canceled)
 32. (canceled)
 33. (canceled)
 34. (canceled)
 35. (canceled)
 36. (canceled)
 37. (canceled)
 38. (canceled)
 39. The composition of claim 1 comprising: DMSO, risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination, and biocompatible poly(L-lactide)-co-(glycolide) (PLGA) copolymer having a lactic acid to glycolic acid monomer ratio ranging from 45:55 to 55:45, wherein: the biocompatible copolymer has a molecular weight in the range of about 30 to about 46 kDa and an inherent viscosity in the range of about 0.25±10% to 0.31±10% dl/g; and the particle size distribution of drug is described by at least one of the following distributions: Parameter I II III IV V VI D0.1 (microns) 27.49  <30 17.41  ≦20  ≦10 ≦10 D0.5 (microns) 79.90 40-130 51.61 40-130 40-130 40-130 D0.9 (microns) 176.66 >170 175.32 >170 >225 >200.


40. The composition of claim 1, wherein, prior to administration, the biocompatible copolymer is irradiated with a dose in the range of about 10 to about 30 kGy of gamma- or beta-radiation measured at a temperature between −40° C. and +35° C.
 41. The composition of claim 40, wherein: a) when the biocompatible polymer has an initial molecular weight of about 50 kDa, it is irradiated with a radiation dose of about 25 KGy to reduce its molecular weight to between about 30 and about 40 kDa; b) when the biocompatible polymer has an initial molecular weight of about 56 kDa, it is irradiated with a radiation dose of about 25 kGy to reduce its molecular weight to between about 30 and about 46 kDa; or c) when the biocompatible polymer has an initial molecular weight of about 63 kDa, it is irradiated with a radiation dose of about 30 kGy to reduce its molecular weight to between about 30 and about 46 kDa.
 42. The composition of claim 1, wherein the particle size distribution of drug is described by at least one of the following distributions: Parameter I II III IV V VI d0.1 (microns) 27.49  <30 17.41  ≦20  ≦10 ≦10 d0.5 (microns) 79.90 40-130 51.61 40-130 40-130 40-130 d0.9 (microns) 176.66 >170 175.32 >170 >225 >200.


43. The composition of claim 1, wherein: a) the mass ratio of drug to (polymer+drug) is in the range of about 25% to about 35%, expressed as the percentage of the drug weight with respect to total weight of the drug plus polymer; b) the mass ratio of drug to final composition is in the range of about 10% to about 15% wt., expressed as the percentage of the weight of drug with respect the total weight of drug plus polymer plus solvent; c) the mass ratio of solvent to drug is in the range of about 12:1 to about 4:1; d) the mass ratio of polymer to polymeric solution expressed as the weight percentage of polymer with respect to the weight of polymer+solvent, is about 25-35% wt or about 30-40% wt; e) the mass ratio of solvent to polymeric solution expressed as the weight percentage of solvent with respect to the weight of polymer plus solvent, is about 60% to about 80% wt; and/or f) the mass ratio of polymer to injectable composition, expressed as the weight percentage of polymer with respect to the weight of polymer plus solvent plus drug, is about 24% to about 34% wt.
 44. (canceled)
 45. (canceled)
 46. (canceled)
 47. (canceled)
 48. (canceled)
 49. (canceled)
 50. (canceled)
 51. (canceled)
 52. (canceled)
 53. (canceled)
 54. (canceled)
 55. The composition of claim 1, wherein the injectable composition releases no more than 20% wt of its charge of paliperidone within 24 hours after being placed in an aqueous environment.
 56. The composition of claim 1, wherein the injectable composition releases at least 0.1% wt of its charge of drug within 24 hours after being placed in an aqueous environment.
 57. (canceled)
 58. The composition of claim 1, wherein ≦20% of the drug is dissolved in the DMSO or polymeric solution to form the injectable composition.
 59. (canceled)
 60. The composition of claim 1, wherein: the particle size distribution of drug is described by at least one of the following distributions: Parameter I II III IV V VI d0.1 (microns) 27.49  <30 17.41  ≦20  ≦10  ≦10 d0.5 (microns) 79.90 40-130 51.61 40-130 40-130 40-130 d0.9 (microns) 176.66 >170 175.32 >170 >225 >200

the mass ratio of drug to (polymer+drug) is in the range of about 25% to about 35%; the mass ratio of drug to final composition is in the range of about 10% to about 15% wt., expressed as the percentage of the weight of drug with respect the total weight of drug plus polymer plus solvent; the mass ratio of solvent to drug is in the range of about 10:1 to about 4:1; the mass ratio of polymer to polymeric solution, expressed as the weight percentage of polymer with respect to the weight of polymer+solvent, is about 25-35% wt; the mass ratio of solvent to polymeric solution, expressed as the weight percentage of solvent with respect to the weight of polymer plus solvent, is about 60% to about 80% wt; the mass ratio of polymer to injectable composition, expressed as the weight percentage of polymer with respect to the weight of polymer plus solvent plus drug, is about 24% to about 34% wt; and >0% to up to about 20% wt. of the drug is dissolved in the DMSO or polymeric solution to form the injectable composition.
 61. The composition of claim 1, wherein: the particle size distribution of drug is described by at least one of the following distributions: Parameter I II III IV V VI d0.1 (microns) 27.49  <30 17.41  ≦20  ≦10  ≦10 d0.5 (microns) 79.90 40-130 51.61 40-130 40-130 40-130 d0.9 (microns) 176.66 >170 175.32 >170 >225 >200

the mass ratio of drug to (polymer+drug) is in the range of about 32% to about 34%; the mass ratio of drug to final composition is in the range of about 12% to about 14% wt., expressed as the percentage of the weight of drug with respect the total weight of drug plus polymer plus solvent; the mass ratio of solvent to drug is in the range of about 5:1 to about 4:1; the mass ratio of polymer to polymeric solution, expressed as the weight percentage of polymer with respect to the weight of polymer+solvent, is about 28 to about 32% wt; the mass ratio of solvent to polymeric solution, expressed as the weight percentage of solvent with respect to the weight of polymer plus solvent, is about 67% to about 72% wt; the mass ratio of polymer to injectable composition, expressed as the weight percentage of polymer with respect to the weight of polymer plus solvent plus drug, is about 25% to about 27% wt; and >0% to up to about 20% wt. of the drug is dissolved in the DMSO or polymeric solution to form the injectable composition.
 62. The composition of claim 1, wherein the injectable composition is prepared by: a) mixing the DMSO and the PLGA copolymer to form a polymeric solution; and b) mixing the paliperidone and the polymeric solution to form the injectable composition. 